Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice.
Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice.
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高剂量辅酶 Q10 制剂对亨廷顿病小鼠的剂量范围和功效研究。
DOI：
10.1016/j.bbadis.2006.03.004
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Ferrante,RobertJ
中科院分区：
文献类型：
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作者：
Smith,KarenM;Matson,Samantha;Matson,WayneR;Cormier,Kerry;DelSignore,StevenJ;Hagerty,SeanW;Stack,EdwardC;Ryu,Hoon;Ferrante,RobertJ
大量证据表明，生物能量缺陷可能在亨廷顿病（HD）的发病机制中起作用。一种潜在的治疗缺陷的能量代谢是线粒体辅因子，辅酶Q10（辅酶Q10）。我们已经报道了辅酶Q10在HD的R6/2转基因小鼠模型中具有神经保护作用。基于CARE-HD试验的令人鼓舞的结果和最近的证据表明，高剂量辅酶Q10减缓帕金森病的进行性功能下降，我们进行了一项剂量范围研究，从两个商业来源的高水平辅酶Q10在R6/2小鼠中，以确定增强的疗效。高剂量辅酶Q10能显著延长R6/2小鼠的存活时间，且其延长程度与剂量和来源有关。辅酶Q10可显著改善R6/2小鼠的运动表现和握力，减轻体重减轻、脑萎缩和亨廷顿蛋白包涵体。与野生型同窝对照小鼠相比，R6/2小鼠脑中CoQ 10和CoQ 9水平显著降低。口服辅酶Q10可提高R6/2小鼠血浆中辅酶Q10的水平，并显著增加脑中辅酶Q9、辅酶Q10和ATP的水平，同时降低氧化损伤的标志物8-羟基-2-脱氧鸟苷的浓度。我们证明，高剂量辅酶Q10的管理发挥更大的治疗效益，在R6/2小鼠的剂量依赖性方式比以前报道的，并建议使用高剂量辅酶Q10的HD患者的临床试验是必要的。
There is substantial evidence that a bioenergetic defect may play a role in the pathogenesis of Huntington's Disease (HD). A potential therapy for remediating defective energy metabolism is the mitochondrial cofactor, coenzyme Q10(CoQ10). We have reported that CoQ10is neuroprotective in the R6/2 transgenic mouse model of HD. Based upon the encouraging results of the CARE-HD trial and recent evidence that high-dose CoQ10slows the progressive functional decline in Parkinson's disease, we performed a dose ranging study administering high levels of CoQ10from two commercial sources in R6/2 mice to determine enhanced efficacy. High dose CoQ10significantly extended survival in R6/2 mice, the degree of which was dose- and source-dependent. CoQ10resulted in a marked improvement in motor performance and grip strength, with a reduction in weight loss, brain atrophy, and huntingtin inclusions in treated R6/2 mice. Brain levels of CoQ10and CoQ9were significantly lower in R6/2 mice, in comparison to wild type littermate control mice. Oral administration of CoQ10elevated CoQ10plasma levels and significantly increased brain levels of CoQ9, CoQ10, and ATP in R6/2 mice, while reducing 8-hydroxy-2-deoxyguanosine concentrations, a marker of oxidative damage. We demonstrate that high-dose administration of CoQ10exerts a greater therapeutic benefit in a dose dependent manner in R6/2 mice than previously reported and suggest that clinical trials using high dose CoQ10in HD patients are warranted.